Nu-[alpha-cyclohexenyl benzyl] piperazines and method of making



N-[a-CYCLOHEXENYL BENZYL] PIPERAZINES AND METHOD OF MAKING Richard Baltzly, Tuckahoe, and Peter B. Russell, Crestwood, N. Y., assignors to Burroughs Wellcome & Co. (U. S. A.) Inc., Tuckahoe, N. Y., a corporation of New York No Drawing. Application July 27, 1954, Serial No. 446,170

8 Claims. (Cl. 260--268) The present invention relates to a family of piperazine derivatives represented by the formula ArCHN NR wherein Ar is a phenyl radical and R is a lower alkyl group. These compounds are prepared from the cisamino alcohols (Formula II) which are described in our copending application Serial No. 409,764 of which this is a continuation-in-part.

Another copending application Serial No. 442,431, filed July 9, 1954, describes the conversion of the trans-aminoalcohols (III) to the corresponding p-toluene sulfonic esters (tosylates). It has been found that when the III cis-aminoalcohols (II) are dissolved in pyridine and reacted with toluene-sulfonyl chloride, no such tosylates can be isolated but rather the aminoalcohols are converted cleanly into the unsaturated compounds (I). The invention also embraces this convenient and unexpected conversion.

The bases and acid addition-salts of Formula I have marked antihistaminic action and the mono-quaternary ammonium salts (IV) are powerful spasmolytics.

ions would be unimportant.

The reaction by which II is converted to I is in efiect an 2,748,127 Patented May 29, 1956 "ice extraordinarily mild dehydration. Such a dehydration, normally produced by acids, is not to be so achieved with these aminoalcohols which are unaltered by moderately drastic treatment with acids and are destroyed by still more vigorous operations. The use of toluene sulfonyl chloride is not critical. This particular sulfonyl chloride is the most readilyavailable. and is entirely satisfactory but other sulfonyl chlorides such as benzene-sulfonyl chloride, p-bromobenzenesulfonyl chloride, methane sulfonyl chloride and ethane sulfonyl chloride behave in exactly the same way.

EXAMPLE I oc- [N '-methyl-N -piperazinobenzyl -cyclohex-A -ene 2-cis-a-[N'-methyl N piperazino]benzylcyclohexanol (17 g.) and p-toluene sulfonyl chloride (31 g.) were mixed in pyridine (100 ml.). After standing overnight, crystals separated which proved to be the p-toluenesulfonate of the starting material. After 100 hours the now homogeneous solution was poured onto ice (700 g.) and the mixture made alkaline with sodium carbonate. The oil was extracted well with ether and the ethereal solution washed with water several times. After being dried the ether was removed and the residue distilled (B. P. 90-95 1 mm. 11 g.) to give a colorless oil.

Hydrogenation of the above base gave an to yield of neutral material. An ethiodide M. P. (dec.) and an isopropyl iodide M. P. 189-190 (dec.) were obtained by the action of the appropriate halide in acetone solution.

EXAMPLE 2 a-[N'-ethyl-N-piperazino]benzocyclohex-A -ene This compound was prepared in a very similar manner to the previous example from 2-cis-a-[N-ethyl-N- piperazino] benzylcyclohexanol (6.7 g.) and p-toluene sulfonyl chloride (13. g.). The product was an oil B. P. 63-65/2 l0 mm. (5 g.). This base with ethyl iodide gave a quaternary salt M. P. 211-212".

EXAMPLE 3 oc- [N '-methyl-N-piperazino] -m-meth0xybenzylcyclolz ex- A -ene This compound was prepared from the corresponding cis-alcohol (3 g.) in the same manner as the above. It boiled at 7075 (0.2 mm.) (1.5 gm.) With ethyl iodide, an ethiodide M. P. 193494 (dec.) was obtained.

What is claimed is:

1. A compound selected from the class consisting of a free base, its nontoxic acid addition salts and its loweralkyl mono-quaternary ammonium salts, said free base having the formula Ar-CH-N NR wherein Ar is a phenyl radical and R is a lower alkyl group.

2. A compound of the formula wherein AI is a phenyl radical and R and R are lower alkyl radicals and X is the anion of a non-toxic acid.

3. The process of preparing an N-[a-A-cyclohexenylbenzyl]N-lower alkyl piperazine which consists of reacting with a reagent selected from the class consisting of 3 4 the aryl and lower alkyl sulfonyl chlorides having not over 4. a-[N-rnethyl-N-pjperazinobenzyl1-cycl0hex-A -ene. seven carbon atoms in an aromatic heterocyclic base as 5. a-[N'-ethyl-N-piperazino]benzylcyclohex-A -ene. solvent a compound of the formula- 6. a-[N-rnthyl-N-piperazino] m methoxybenzylcyclohex-A -ene. Ar-CHN N-R 5 7. A nontoxic salt ofthe N-methyl-N-ethyl-N [u-(A' cyclohexenyl) benzyl] piperazinium ion.

8. a nontoxic salt of the N, N-diethyl-N [A' cyclog t? hexenyl benzyl] piperazinium ion.

No references cited. wherein Ar is a phenyl radical and R is a lower alkyl group. 

1. A COMPOUND SELECTED FROM THE CLASS CONSISTING OF A FREE BASE, ITS NONTOXIC ACID ADDITION SALTS AND ITS LOWERALKYL MONO-QUATERNARY AMMONIUM SALTS, SAID FREE BASE HAVING THE FORMULA-
 3. THE PROCESS OF PREPARING AN N-(A-)''-CYCLOHEXENYLBENZYL)N''-LOWER ALKYL PIPERAZINE WHICH CONSISTS OF REACTING WITH A REAGENT SELECTED FROM THE CLASS CONSISTING OF THE ARYL AND LOWER ALKYL SULFONYL CHLORIDES HAVING NOT OVER SEVEN CARBON ATOMS IN AN AROMATIC HETEROCYCLIC BASE AS SOLVENT A COMPOUND OF THE FORMULA- 